Preliminary evidence that negative symptom severity relates to multilocus genetic profile for dopamine signaling capacity and D2 receptor binding in healthy controls and in schizophrenia

Abstract

Deficits in central, subcortical dopamine (DA) signaling may underlie negative symptom severity, particularly anhedonia, in healthy individuals and in schizophrenia. To investigate these relationships, we assessed negative symptoms with the Schedule for the Assessment of Negative Symptoms and the Brief Negative Symptom Scale (BNSS) and self-reported anhedonia with the Scales for Physical and Social Anhedonia (SPSA), Temporal Experience of Pleasure Scale, and Snaith-Hamilton Pleasure Scale in 36 healthy controls (HC), 27 siblings (SIB) of individuals with schizophrenia, and 66 individuals with schizophrenia or schizoaffective disorder (SCZ). A subset of participants (N = 124) were genotyped for DA-related polymorphisms in genes for DRD4, DRD2/ANKK1, DAT1, and COMT, which were used to construct biologically-informed multi-locus genetic profile (MGP) scores reflective of subcortical dopaminergic signaling. DA receptor type 2 (D2R) binding was assessed among a second subset of participants (N = 23) using PET scans with the D2R-selective, non-displaceable radioligand (N-[¹¹C]methyl)benperidol. Higher MGP scores, reflecting elevated subcortical dopaminergic signaling capacity, were associated with less negative symptom severity, as measured by the BNSS, across all participants. In addition, higher striatal D2R binding was associated with less physical and social anhedonia, as measured by the SPSA, across HC, SIB, and SCZ. The current preliminary findings support the hypothesis that subcortical DA function may contribute to negative symptom severity and self-reported anhedonia, independent of diagnostic status.

Introduction

The etiology of schizophrenia remains unclear but central dopamine (DA) transmission likely plays a role in its manifestation. Positive symptoms may be due in part to mesostriatal DA dysfunction (Brisch et al., 2014, Howes and Nour, 2016, Kapur, 2003), characterized by elevated striatal DA synthesis capacity and synaptic DA availability (Howes et al., 2012, Laruelle et al., 1999, Reith et al., 1994) which may in turn confer aberrant incentive salience onto non-relevant stimuli (Heinz, 2002, Robinson and Berridge, 1993, Schultz et al., 1997). By contrast, negative symptoms are posited to arise in part from hypodopaminergic transmission in prefrontal cortex (Davis et al., 1991, Goghari et al., 2010, Heinz, 2002, Knable and Weinberger, 1997). In addition, fMRI studies have shown that negative symptoms, especially those in the motivational dimension such as anhedonia, relate to blunted blood oxygen level-dependent (BOLD) reward-related activation in striatum among patients (Dowd and Barch, 2010, Dowd and Barch, 2012, Juckel et al., 2006b, Simon et al., 2010, Waltz et al., 2009, Waltz et al., 2010) and healthy individuals (Corral-Frías et al., 2015). Negative symptoms may also be risk factors for depression (Kupferberg et al., 2016) and substance abuse (Leventhal et al., 2010) in healthy individuals. The role of striatal DA transmission in negative symptom severity therefore merits further investigation.

The study of DA-related genetic polymorphisms may aid in understanding the role of DA signaling in both positive and negative symptom severity in schizophrenia. The disease is 80–85% heritable (Cardno and Gottesman, 2000) and common DA-related polymorphisms have been associated with variability in DA signaling (Asghari et al., 1995, Gluskin and Mickey, 2016, Heinz et al., 2000, Meyer-Lindenberg et al., 2005, Thompson et al., 1997). DA-related multilocus genetic profiles (MGPs) are composites of several DA-related polymorphisms and putatively predict ‘net’ DA function. Such DA-related MGPs have been associated with striatal BOLD responsivity to reward (Nikolova et al., 2011, Stice et al., 2012), addictive behavior and personality (Davis and Loxton, 2013), food addiction, emotional and hedonic eating (Davis et al., 2013), and depression (Pearson-Fuhrhop et al., 2014). To our knowledge, MGPs have not yet been used to study the role of subcortical DA signaling in symptom severity in schizophrenia or in healthy individuals.

Investigation of striatal D2 receptors (D2R) may yield further insight into the link between symptom severity and striatal DA function. Some studies have found increased striatal D2/D3 receptor (D2/D3R) availability in schizophrenia compared to non-diseased individuals but many others have not (Howes et al., 2012). Alternatively, symptom severity may more strongly relate to D2/D3R availability than patient status. Low striatal D2/D3R availability in patients, either at baseline or due to receptor occupancy by antipsychotics, has been associated with greater negative symptom severity (de Haan et al., 2000, Heinz et al., 1998, Lataster et al., 2011, Martinot et al., 1994, Pickar et al., 1996, Uchida et al., 2009) and dysphoria (Mizrahi et al., 2007). However, it has also been associated with greater positive and less negative symptom severity (Pogarell et al., 2012) and some studies did not show any relationship (Agid et al., 2007, Graff-Guerrero et al., 2009, Kegeles et al., 2008, Klemm et al., 1996, Talvik et al., 2006). Some of the variability in these findings may be due to certain properties of the D2/D3R radioligands used (i.e. [¹¹C]raclopride, [¹²³I]iodobenzamide). First, these radiligands do not distinguish between D2R and D3R (Elsinga et al., 2006, Mukherjee et al., 1999, Videbaek et al., 2000). While their distribution overlaps, these receptor subtypes are preferentially localized to different brain regions. Therefore, D2R and D3R may have distinct functional roles in symptom severity. Second, these radioligands are vulnerable to displacement by endogenous DA (Dewey et al., 1992, Laruelle et al., 1995, Riccardi et al., 2006), confounding interpretation of PET measures of in vivo D2/D3R availability. The relationship between symptom severity and striatal D2R using a non-displaceable, D2R-selective PET radioligand has not yet been studied in individuals with schizophrenia or in healthy individuals.

Here, we studied positive and negative symptom severity, with an emphasis on self-reported anhedonia, in healthy controls (HC), siblings of individuals with schizophrenia (SIB), and individuals with schizophrenia or schizoaffective disorder (SCZ). Unaffected siblings provide the opportunity to study relationships among variables of interest in individuals who share genes with their affected siblings but are medication-naïve. First, we tested the hypothesis that MGP scores, which were composites of DA-related genotypes and formulated to reflect genetically regulated subcortical DA signaling capacity (Stice et al., 2012), would relate to symptom severity and self-reported anhedonia. Specifically, based on evidence of striatal hyperdopaminergic signaling in schizophrenia (Howes et al., 2012, Laruelle et al., 1999, Reith et al., 1994) and a lack of direct evidence for striatal hypodopaminergic signaling in association with symptom severity, we hypothesized that lower MGP scores that reflect lower subcortical DA signaling capacity would relate to lower levels of both positive and negative symptom severity and less self-reported anhedonia across HC, SIB, and SCZ. Second, using a novel D2R-selective PET radioligand that is not displaceable by endogenous DA, (N-[¹¹C]methyl)benperidol ([¹¹C]NMB), we tested the hypothesis that lower striatal D2R specific binding would relate to lower symptom severity and less self-reported anhedonia in a subset of HC, SIB, and unmedicated SCZ.